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Abstract Therapeutic development for skeletal muscle diseases is challenged by a lack of ex vivo models that recapitulate human muscle physiology. Here, we engineered 3D human skeletal muscle tissue in the Biowire II platform that could be maintained and electrically stimulated long‐term. Increasing differentiation time enhanced myotube formation, modulated myogenic gene expression, and increased twitch and tetanic forces. When we mimicked exercise training by applying chronic electrical stimulation, the “exercised” skeletal muscle tissues showed increased myotube size and a contractility profile, fatigue resistance, and gene expression changes comparable to in vivo models of exercise training. Additionally, tissues also responded with expected physiological changes to known pharmacological treatment. To our knowledge, this is the first evidence of a human engineered 3D skeletal muscle tissue that recapitulates in vivo models of exercise. By recapitulating key features of human skeletal muscle, we demonstrated that the Biowire II platform may be used by the pharmaceutical industry as a model for identifying and optimizing therapeutic drug candidates that modulate skeletal muscle function.

Abstract The role of C‐type natriuretic peptide (CNP) in the regulation of cardiac function in humans remains to be established as previous investigations have been confined to animal model systems. Here, we used well‐characterized engineered cardiac tissues (ECTs) generated from human stem cell‐derived cardiomyocytes and fibroblasts to study the acute effects of CNP on contractility. Application of CNP elicited a positive inotropic response as evidenced by increases in maximum twitch amplitude, maximum contraction slope and maximum calcium amplitude. This inotropic response was accompanied by a positive lusitropic response as demonstrated by reductions in time from peak contraction to 90% of relaxation and time from peak calcium transient to 90% of decay that paralleled increases in maximum contraction decay slope and maximum calcium decay slope. To establish translatability, CNP‐induced changes in contractility were also assessed in rat ex vivo (isolated heart) and in vivo models. Here, the effects on force kinetics observed in ECTs mirrored those observed in both the ex vivo and in vivo model systems, whereas the increase in maximal force generation with CNP application was only detected in ECTs. In conclusion, CNP induces a positive inotropic and lusitropic response in ECTs, thus supporting an important role for CNP in the regulation of human cardiac function. The high degree of translatability between ECTs, ex vivo and in vivo models further supports a regulatory role for CNP and expands the current understanding of the translational value of human ECTs.